CN1318032C - Ethinyl estradiol gas permeable absorbing paste - Google Patents
Ethinyl estradiol gas permeable absorbing paste Download PDFInfo
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- CN1318032C CN1318032C CNB2005100489983A CN200510048998A CN1318032C CN 1318032 C CN1318032 C CN 1318032C CN B2005100489983 A CNB2005100489983 A CN B2005100489983A CN 200510048998 A CN200510048998 A CN 200510048998A CN 1318032 C CN1318032 C CN 1318032C
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Abstract
The present invention provides an ethynyl estradiol percutaneous absorption applicator which is a flaky percutaneous absorption preparation prepared by stacking a back lining layer, a medicine substrate layer and a protective film and can be used for the alleviative treatment of prostatic cancer. The applicator of the present invention has the advantages of high ethynyl estradiol percutaneous velocity, good penetration effect and treatment requirement satisfaction. The ethynyl estradiol is supplied through a percutaneous penetration approach to prolong medicien action time, keep stable blood medicine concentration and reduce medicine side effect and the ethynyl estradiol percutaneous quantity of each applicator (20cm<2>) per day can reach about 80 to 360 mug. In addition, the present invention has the advantages of convenient use, high safety and high efficiency.
Description
Technical field
The invention belongs to the pharmaceutics field, relate to the drug transdermal absorption adhesive patch, relate in particular to ethinyl estradiol gas permeable absorbing paste.
Background technology
Cancer is the maximum disease that the mankind face.For the male, the male more than more than 40 year old particularly, the sickness rate of carcinoma of prostate is to arrange before all kinds of malignant tumor.Along with the decline of aged tendency of population and mortality rate, make the sickness rate of carcinoma of prostate with average 8% rate increase, expect 2011, the sickness rate of carcinoma of prostate will double.Only the U.S. will reach about 2,900,000 people, and China also will be about 8,000,000 people.For the carcinoma of prostate of the transfer in late period, can be by hormone therapy mitigation symptoms, the quality of making the life better.The androgen receptor of carcinoma of prostate is positioned at cytoplasm, and testosterone (T) and metabolite dihydrotestosterone (DHT) thereof are the strongest parts of its biological activity.Testosterone derives from the Leydig cell of testis, and its synthetic excretory lutropin of hypophysis (LH) that is subjected to is controlled.Estrogen is the strongest inhibitive factor that hypophysis lutropin (LH) discharges, and plays a role by the level that reduces testosterone in the blood plasma.Bibliographical information, every day, the diethylstilbestrol of 3mg can make that testosterone extremely reduces in the blood, as the level after the testosterone excision.And biological activity ratio's diethylstilbestrol of ethinylestradiol is strong 300 times.Ethinylestradiol can also directly suppress the generation of testosterone steroid hormone, and influences the metabolism of prostata tissue.Be used for the carcinoma of prostate palliative treatment in the market and have only oral tablet, not other dosage form listings.The ethinylestradiol molecular weight is 296.41, and is fat-soluble, is a kind of comparatively ideal percutaneous dosing drug candidate.
Summary of the invention
The purpose of this invention is to provide a kind of ethinyl estradiol gas permeable absorbing paste; ethinyl estradiol gas permeable absorbing paste of the present invention is stacked the laminar transdermal absorption formulation of forming by backing layer, drug matrices layer and protecting film; the drug matrices layer comprises pressure sensitive adhesive solution, medicine ethinylestradiol and skin penetration enhancer, has drug depot and adheres to two functions.Comprise in the hypothallus: (1) medicine ethinylestradiol, its content accounts for the 0.5-10% of hypothallus gross weight; (2) pressure sensitive adhesive requires medicine ethinylestradiol inertia, employing be polyacrylate pressure-sensitive, its content accounts for the 30-90% of hypothallus gross weight; (3) plasticizer, its effect are to insert between the molecule segment of pressure sensitive adhesive polymer, weaken interchain interaction force, increase chain flexibility, make that the short motion of chain is relatively easy.What the present invention used is dibutyl sebacate or triethyl citrate, and its content accounts for the l5-30% of hypothallus gross weight, and optimum content is 19-25%; (4) cross-linking agent, its effect are the affinitys that improves between polymer monomer, reduce the migration trend of paster.The present invention selects succinic acid for use, and the uncle of its carboxyl and polyacrylate is amino to interact, and two adjacent polymer segments are linked to each other, thereby has improved the character of system.Succinic acid content accounts for the 1-7% of hypothallus gross weight, and optimum content is 3-5%; (5) skin penetration enhancer, its effect is the percutaneous permeability that improves ethinylestradiol, and what the present invention selected for use is oleic acid, isopropyl myristate, and is short effective thoroughly, its content accounts for 10-40%, the 10-40% of hypothallus gross weight respectively, and optimum content is 13.9-32.3%, 13.9-20.5%.Conventional paster is divided into two kinds of reservoir devices and matrix types.Reservoir devices is that medicine or transdermal absorption accelerator are rolled into the storage storehouse by release-controlled film or other controlled-release materials, by the character control release rate of drugs of release-controlled film or control material.Matrix type is medicine dissolution or is dispersed in the polymer backbone, is controlled the release of medicine by the constituent of skeleton.This paster belongs to the adhesive matrix type, also is a kind of of matrix type.
Ethinylestradiol of the present invention has following structural:
Ethinyl estradiol gas permeable absorbing paste provided by the invention can be used as carcinoma of prostate palliative treatment medicine.
This class transdermal patch is known in this area.Hypothallus and protecting film that it comprises backing layer, contain medicine stack composition.Hypothallus is fixed on this paster on the skin as drug reservoir and by it.It is pliable and tough that backing layer requires, and is attached on the skin soft comfortablely, works to cover and protect drug depot.Before the use, protecting film will be torn off.
Hypothallus comprises pressure sensitive adhesive, medicine ethinylestradiol and skin penetration enhancer, has drug depot and adheres to two functions.Hypothallus of the present invention adopts polyacrylate, mainly be that employing is the controlled release matrix material with the polyacrylate pressure-sensitive, the ethinylestradiol of doses and oleic acid or isopropyl myristate are dissolved in the solution of polyacrylate, make with ethinylestradiol by solvent evaporation method to be uniformly distributed in the skeleton.Regulate the ethinylestradiol rate of release of paster by the content that changes pressure sensitive adhesive, medicine and penetration enhancer in the hypothallus.
Protecting film is selected polyethylene, polystyrene, polypropylene, polyester film, silication polyester film, aluminium foil, silication aluminium foil, silicon paper for use.
Can prepare paster of the present invention with known step in the transdermal patch field.This step generally comprises preparation substrate (being mixed adhesive, medicine, penetration enhancer and additive); substrate is applied on protecting film or the backing; then dried except that after the cooling of desolvating, contains ethinylestradiol 0.1-1mg in every square centimeter the paster from this substrate.
The invention has the beneficial effects as follows: (1) by the transdermal penetration administration, prolong drug action time keeps stable blood drug level with ethinylestradiol, reduces side effects of pharmaceutical drugs.Each paster (20cm
2) every day transdermal ethinylestradiol amount can reach about 80-360 μ g.(2) use oleic acid or isopropyl myristate etc. to be penetrating agent, increased the percutaneous rate of ethinylestradiol, make it satisfy the treatment requirement.(3) easy to use, safe, effective.
Description of drawings
Fig. 1 is drug accumulation infiltration capacity-time graph of embodiment 1
Fig. 2 is drug accumulation infiltration capacity-time graph of embodiment 2
Fig. 3 is drug accumulation infiltration capacity-time graph of embodiment 3
Fig. 4 is drug accumulation infiltration capacity-time graph of embodiment 4
Fig. 5 is drug accumulation infiltration capacity-time graph of embodiment 5
Fig. 6 is the system schematic of this paster
The specific embodiment
The present invention is further elaborated by following embodiment.Except as otherwise noted, described percentage ratio is by total amount.
Embodiment 1
Polyacrylate pressure-sensitive (PSA) 390mg, dibutyl sebacate 175mg, succinic acid 35mg, medicine ethinylestradiol 20mg, oleic acid 160mg, and solvent (acetone: isopropyl alcohol: 2400mg ethanol=21: 2.3: 11.7), put into bottle together, the bottleneck sealing after dissolving fully, is coated on 40cm
2Backing layer on, then 60 ℃ of dry 30min.Dried hypothallus contains polyacrylate 50%, ethinylestradiol 2.6%, oleic acid 20.5%, the cooling back covers goes up backing layer, adopt improvement Franz diffusion cell device to measure its permeability to people's isolated skin, acceptable solution is 20% PEG400 (PEG400) normal saline aqueous solution.Measure ethinylestradiol with HPLC, wavelength is 281nm, and mobile phase is 70% methanol, and 30% water, flow velocity are 1ml/min, and to ethinylestradiol, retention time is about 5.5min, and infiltration rate is 0.76ug/cm
2H.Fig. 1 is drug accumulation infiltration capacity-time graph of this embodiment.
Polyacrylate pressure-sensitive (PSA) 390mg, dibutyl sebacate 175mg, succinic acid 35mg, medicine ethinylestradiol 20mg, oleic acid 100mg, solvent (acetone: isopropyl alcohol: 2400mg ethanol=21: 2.3: 11.7), as 1 operation, dried hypothallus contains polyacrylate 54%, ethinylestradiol 2.8%, oleic acid 13.9%, the cooling back covers goes up backing layer, adopt improvement Franz diffusion cell device to measure its permeability to people's isolated skin, acceptable solution is 20% PEG400 (PEG400) normal saline aqueous solution, and infiltration rate is 0.50ug/cm
2H.Fig. 2 is drug accumulation infiltration capacity-time graph of this embodiment.
Polyacrylate pressure-sensitive (PSA) 300mg, dibutyl sebacate 135mg, succinic acid 27mg, medicine ethinylestradiol 20mg, oleic acid 230mg, solvent (acetone: isopropyl alcohol: 1848mg ethanol=21: 2.3: 11.7), as 1 operation, dried hypothallus contains polyacrylate 42%, ethinylestradiol 2.8%, oleic acid 32.3%, the cooling back covers goes up backing layer, adopt improvement Franz diffusion cell device to measure its permeability to people's isolated skin, acceptable solution is 20% PEG400 (PEG400) normal saline aqueous solution, and infiltration rate is 0.43ug/cm
2H.Fig. 3 is drug accumulation infiltration capacity-time graph of this embodiment.
Embodiment 4
Eudragit E100 (butyl methacrylate-methacrylic acid-2-methylamino ethyl ester-methylmethacrylate copolymer (1: 2; 1)) 390mg, dibutyl sebacate 175mg, succinic acid 35mg, medicine ethinylestradiol 20mg, IPM 160mg, solvent (acetone: isopropyl alcohol: 2400mg ethanol=21: 2.3: 11.7), as 1 operation, dried hypothallus contains polyacrylate 54%, ethinylestradiol 2.8%, and IPM 20.5%, the cooling back covers goes up backing layer, adopt improvement Franz diffusion cell device to measure its permeability to people's isolated skin, acceptable solution is 20% PEG400 (PEG400) normal saline aqueous solution, and infiltration rate is 0.23ug/cm
2H.Fig. 4 is drug accumulation infiltration capacity-time graph of this embodiment.
Polyacrylate pressure-sensitive (PSA) 390mg, dibutyl sebacate 175mg, succinic acid 35mg, medicine ethinylestradiol 20mg, IPM 100mg, solvent (acetone: isopropyl alcohol: 2400mg ethanol=21: 2.3: 11.7), as 1 operation, dried hypothallus contains polyacrylate 54%, ethinylestradiol 2.8%, and IPM 13.9%, the cooling back covers goes up backing layer, adopt improvement Franz diffusion cell device to measure its permeability to people's isolated skin, acceptable solution is 20% PEG400 (PEG400) normal saline aqueous solution, and infiltration rate is 0.17ug/cm
2H.Fig. 5 is drug accumulation infiltration capacity-time graph of this embodiment.
Need not further to elaborate, believe and adopt the disclosed content in front, those skilled in the art can use to greatest extent.Therefore, the preferred specific embodiments of front should be understood that only to illustrate, but not limits the scope of the invention by any way.
Claims (2)
1. ethinyl estradiol gas permeable absorbing paste; stack by backing layer, the hypothallus that contains medicine and protecting film and to form; it is characterized in that: the drug matrices layer comprises pressure sensitive adhesive, medicine ethinylestradiol, skin penetration enhancer, plasticizer, cross-linking agent, and wherein ethinylestradiol has following structural
Ethinylestradiol content accounts for the 0.5-10% of hypothallus gross weight, pressure sensitive adhesive adopts polyacrylate pressure-sensitive, its content accounts for the 30-90% of hypothallus gross weight, the skin penetration enhancer is selected isopropyl myristate or oleic acid for use, the two content accounts for 10-40%, the 10-40% of hypothallus gross weight successively respectively, and plasticizer is dibutyl sebacate or triethyl citrate, and content accounts for the 15-30% of hypothallus gross weight, cross-linking agent is a succinic acid, and its content accounts for the 1-7% of hypothallus gross weight.
2. ethinyl estradiol gas permeable absorbing paste according to claim 1 is characterized in that: protecting film is selected polyethylene, polystyrene, polypropylene, polyester film, silication polyester film, aluminium foil, silication aluminium foil, silicon paper for use.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2005100489983A CN1318032C (en) | 2005-01-24 | 2005-01-24 | Ethinyl estradiol gas permeable absorbing paste |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2005100489983A CN1318032C (en) | 2005-01-24 | 2005-01-24 | Ethinyl estradiol gas permeable absorbing paste |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1679589A CN1679589A (en) | 2005-10-12 |
| CN1318032C true CN1318032C (en) | 2007-05-30 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB2005100489983A Expired - Fee Related CN1318032C (en) | 2005-01-24 | 2005-01-24 | Ethinyl estradiol gas permeable absorbing paste |
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Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100413501C (en) * | 2006-03-06 | 2008-08-27 | 浙江大学 | Transdermal absorptive anemonin plaster |
| CN101366705B (en) * | 2008-09-28 | 2010-09-08 | 浙江大学 | Risperidone percutaneous absorption paster |
| CN105078928A (en) * | 2014-05-08 | 2015-11-25 | 广东省中药研究所 | Nisoldipine ethosome controlled-released patch and preparation method thereof |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4816258A (en) * | 1987-02-26 | 1989-03-28 | Alza Corporation | Transdermal contraceptive formulations |
| CN1190351A (en) * | 1995-06-07 | 1998-08-12 | 西格纳斯公司 | Transdermal patch and method for administering 17-deacetyl norgestimate alone or in combination with estrogen |
| CN1399533A (en) * | 1999-11-24 | 2003-02-26 | 敏捷治疗公司 | Improved transdermal contraceptive delivery system and process |
-
2005
- 2005-01-24 CN CNB2005100489983A patent/CN1318032C/en not_active Expired - Fee Related
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4816258A (en) * | 1987-02-26 | 1989-03-28 | Alza Corporation | Transdermal contraceptive formulations |
| CN1190351A (en) * | 1995-06-07 | 1998-08-12 | 西格纳斯公司 | Transdermal patch and method for administering 17-deacetyl norgestimate alone or in combination with estrogen |
| CN1399533A (en) * | 1999-11-24 | 2003-02-26 | 敏捷治疗公司 | Improved transdermal contraceptive delivery system and process |
Non-Patent Citations (1)
| Title |
|---|
| The trandermal contraceptive system Ronald T.et al,American Journal of Obstetris and Gynecology,Vol.190 2004 * |
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| CN1679589A (en) | 2005-10-12 |
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Assignee: Zhenjiang Dingtai Pharmaceutical Co., Ltd. Assignor: Zhejiang University Contract fulfillment period: 2007.11.20 to 2012.11.19 contract change Contract record no.: 2008330002479 Denomination of invention: Ethinyl estradiol gas permeable absorbing paste Granted publication date: 20070530 License type: Exclusive license Record date: 2008.12.1 |
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Free format text: EXCLUSIVE LICENSE; TIME LIMIT OF IMPLEMENTING CONTACT: 2007.11.20 TO 2012.11.19; CHANGE OF CONTRACT Name of requester: ZHEJIANG PROVINCE DINGTAI PHARMACEUTICAL CO., LTD. Effective date: 20081201 |
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| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20070530 Termination date: 20110124 |